1. Field of the Invention
This invention relates to novel compounds having the cephem nucleus and a fluorine on the methyl side chain at the 3-position and a novel method for the preparation of such compounds having up to 2 fluorines at this position.
2. Description of the Prior Art
In general, cephalosporins are antibiotics related to penicillin except that the cephalosporins are often effective against penicillin resistant organisms. They have drawbacks however in having lower oral absorption and lower activity and various attempts have been made to improve these properties through chemical modification of the cephalosporin molecule.
The cephalosporin C nucleus can be named as 1-aza-5-thia-6R-bicyclo[4,2,0]octan-8-one, although cepham or cephem (for .DELTA..sup.2 or .DELTA..sup.3 -unsaturate) is simpler and easier to use for the compounds. The structure of cephalosporanic acid is ##SPC1##
A halogen derivative, 3-bromomethyl (prepared by N-bromosuccinimide on 3-methyl cephem) has been proposed in South African Pat. No. 6900,761. Other recently issued patents such as Netherlands Pat. No. 7,004,479 and French Pat. No. 1,589,109 disclose 3-halomethyl derivatives where the halogen is specified as Cl, Br or I. Recent West German Pat. No. 2,052,531 appears to disclose the monofluoro derivative but does not give any method of fluorine-containing reagents whereby such monofluoro derivative would be obtainable. It is widely recognized that properties and synthetic methods for preparing fluoro compounds are quite different than for the other halogens. No mention is made in the art of polyhalo derivatives, much less the difluoromethyl compound.
The cephalosporin ring system includes a .beta.-lactam ring fused to nitrogen of a thiazine ring system. Some of these ring systems are unstable to hydrolysis and fluorination conditions. Furthermore polyhalogen derivatives are generally hydrolytically unstable and it is not surprising that in this field of antibiotic transformations no processes have been suggested for fluorination of cephalosporins.